P659: IBRUTINIB IN OVER-EIGHTIES PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: A MULTICENTER ITALIAN COHORT
Authors: G. Reda, V. Mattiello, A. M. Frustaci, A. Visentin, F. R. Mauro, I. Innocenti, M. Gentile, D. Giannarelli, A. Noto, R. Cassin, L. Laurenti, A. Tedeschi
Journal: HemaSphere (2022)

Background: Ibrutinib is a first-in-class covalent inhibitor of Bruton’s tyrosine kinase that has changed the treatment paradigm of chronic lymphocytic leukemia (CLL) in both treatment-naive (TN) and relapsed/refractory (R/R) setting. Clinical trials, in selected populations showed that the BTK inhibitor is manageble even in the elderly. Nevertheless, few studies are focused on the role of ibrutinib in unselected patients aged ≥80 years. Aims: We aimed to assess the activity and safety of ibrutinib in a cohort of patients with CLL aged ≥80 years at therapy start. The primary endpoint was safety evaluation. Key secondary endpoints were overall (ORR), complete (CR) and partial (PR) response rates according to iwCLL 2018, median progression free survival (PFS) and overall survival (OS). Methods: Sixty consecutive patients (age ≥80 years) diagnosed with TN (20 patients) or R/R CLL (40 patients) who started ibrutinib were enrolled in this multicenter study from six Italian sites; data were retrospectively analyzed. Pre-existing cardiovascular risk factors were present in 66.7% of patients; 23.3% had experienced a cardiovascular event prior ibrutinib initiation. (Table 1) Results: After a median follow up of 27 months, at least one adverse event (AE) occurred in 68.3% patients, leading to treatment discontinuation in 23.3%. The most common grade ≥3 events were infections (23%) and neutropenia (6%). Cardiovascular events occurred in 31.6% of patients, with an incidence of atrial fibrillation (AF) and arterial hypertension both increasing over time and reaching 16% at 24 months. Although no significant increase in incidence of cardiovascular events was noted among patients with concomitant cardiovascular risk factors or previous events, baseline higher left atrial diameter at echocardiography was predictive of AF occurrence. OS did not differ between patients experiencing AF or not. During treatment, two patients experienced sudden cardiac death. Bleeding was the most frequent AE, occurring in 36.6% of patients, with a median time to event of 24 months and predominantly in patients assuming concomitant antiplatelet or anticoagulant drugs. A total of 23 infective events was registered, mostly in the first 12 months, leading to drug permanent discontinuation in 5 patients. Of note, the infectious rate was higher in del(17p) CLL (p=0.05). The obtained ORR was 88.3%, with 21.7% of patients achieving CR and 66.7% PR; median PFS was 51.8 months (95% CI: 47.4-56.2). No significant difference in PFS was observed comparing TN to R/R patients (p=0.83), or IGHV mutated and unmutated patients (p=0.45). Furthermore, no difference emerged comparing PFS data of patients with TP53 dysfunction (del17 and/or TP53 mutation) to patients without TP53 dysfunction (p=0.13). Patients achieving a response during ibrutinib experienced a prolonged PFS compared to patients achieving SD (p<0.0001). Drug withholding for more than 7 days due to ibrutinib-related toxicities affected patients’ outcome, translating in a shorter PFS with a trend to statistical significance (p=0.07). Median overall survival was 53.2 months (95% CI: 43.3-63.0). Image:Summary/Conclusion: A high proportion of patients had an overall response to ibrutinib and the risk-benefit profile was favourable, providing further evidence for use of ibrutinib in this subset of elderly and unselected patients. Safety profile remains consistent with literature data with no emergent adverse events, thus making ibrutinib an attractive therapeutic possibility even in patients with advanced age and multiple comorbidities.